A1 adenosine receptor upregulation accompanies decreasing myocardial adenosine levels in mice with left ventricular dysfunction

Hajime Funakoshi, Lefteris C. Zacharia, Zhonghua Tang, Jin Zhang, Ling L. Lee, Julie C. Good, David E. Herrmann, Yoshihiro Higuchi, Walter J. Koch, Edwin K. Jackson, Tung O. Chan, Arthur M. Feldman

Research output: Contribution to journalArticlepeer-review

34 Citations (Scopus)

Abstract

BACKGROUND - It is well known that adenosine levels are increased during ischemia and protect the heart during ischemia/reperfusion. However, less is known about the role of adenosine-adenosine receptor (AR) pathways in hearts with left ventricular dilation and dysfunction. Therefore, we assessed adenosine levels and selective AR expression in transgenic mice with left ventricular systolic dysfunction secondary to overexpression of tumor necrosis factor-α (TNF 1.6). METHODS AND RESULTS - Cardiac adenosine levels were reduced by 70% at 3 and 6 weeks of age in TNF 1.6 mice. This change was accompanied by a 4-fold increase in the levels of A1-AR and a 50% reduction in the levels of A2A-AR. That the increase in A1-AR density was of physiological significance was shown by the fact that chronotropic responsiveness to the A1-AR selective agonist 2-chloro-N-cyclopentanyladenosine was enhanced in the TNF 1.6 mice. Similar changes in adenosine levels were found in 2 other models of heart failure, mice overexpressing calsequestrin and mice after chronic pressure overload, suggesting that the changes in adenosine-AR signaling were secondary to myocardial dysfunction rather than to TNF overexpression. CONCLUSIONS - Cardiac dysfunction secondary to the overexpression of TNF is associated with marked alterations in myocardial levels of adenosine and ARs. Modulation of the myocardial adenosine system and its signaling pathways may be a novel therapeutic target in patients with heart failure.

Original languageEnglish
Pages (from-to)2307-2315
Number of pages9
JournalCirculation
Volume115
Issue number17
DOIs
Publication statusPublished - May 2007

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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